CD28 CO-STIMULATION IS INTACT AND CONTRIBUTES TO PROLONGED EX-VIVO SURVIVAL OF HYPORESPONSIVE SYNOVIAL-FLUID T-CELLS IN RHEUMATOID-ARTHRITIS

In rheumatoid arthritis (RA), T cells in the inflamed joint are consid ered to play a crucial role in the pathogenesis. However, despite the fact that synovial T cells have an activated memory phenotype, they ar e functionally suppressed upon combined CD3 and CD28 stimulation. Here , we analyzed the contribution of both CD3 and CD28 to the hyporespons iveness of synovial T cells in RA. In contrast to the low CD3 responsi veness of synovial fluid (SF)T cells compared to peripheral blood (PB) T cells, the CD28 co-stimulatory response was observed to be unaffecte d. Hyporesponsiveness of SF T cells has previously been associated wit h decreased levels of intracellular glutathione (GSH), an antioxidant and regulator of the intracellular redox state. Treatment of SF T cell s with N-acetylcysteine, an antioxidant and replenisher of GSH, select ively improved CD3-induced responses, while leaving CD28 responsivenes s unaffected. These data show that the CD3 pathway is highly sensitive to intracellular GSH alterations, whereas CD28 responsiveness is rela tively refractory. Furthermore, in support for a functional role of CD 28 co-stimulation, it was demonstrated that CD28 ligation acted in syn ergy with the IL-2 receptor gamma chain signaling cytokine IL-15 in th e enhancement of the ex vivo survival of SF T cells. These data indica te that CD28 co-stimulatory capacity of SF T cells, in contrast to CD3 stimulation, remains intact despite an altered intracellular redox st ate. Thereby, CD28 stimulation may contribute to the persistence of T cells at the site of inflammation, which might be of relevance in the pathogenesis of RA.